Carbidopa-Levodopa in Dry Age Related Macular Degeneration With Geographic Atrophy
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 7
- 试验地点
- 1
- 主要终点
- Area of Geographic Atrophy
研究概览
简要总结
From 3 large patient databases, patients diagnosed with AMD who have never taken levodopa(L-DOPA) containing medications have a mean age of diagnosis at 71 years.
Patients who have been treated with L-DOPA containing medications have a mean age of diagnosis of AMD at 79 years. L-DOPA binds to GPR143 in the retinal pigment epithelium, and releases PEDF, which protects the retina and downregulates VEGF, which is the cause of neovascularization.
The Investigators will evaluate the safety and tolerability of carbidopa-levodopa in patients with Neovascular AMD, and measure the effects on visual acuity and retinal abnormalities due to "wet" (neovascular) AMD. The Investigators will evaluate the safety and tolerability of carbidopa-levodopa in patients with Dry AMD and Geographic Atrophy, and measure the effects on visual acuity, area of geographic atrophy and other retinal abnormalities due to "dry" AMD.
详细描述
Age-related macular degeneration (AMD) is the most common cause of blindness, in individuals over the age of 50, in the developed world. AMD becomes more common as people age, and is more common in lightly pigmented individuals. AMD appears more common in patients with Parkinson's Disease, than in those without. The AREDS nutritional supplements are effective in slowing the progress of intermediate AMD(5).
Most AMD is "dry AMD", which progresses relatively slowly and may impair vision, but usually does not lead to legal blindness. There are two forms of AMD, "wet AMD" and geographic atrophy (GA), that can cause more profound vision loss. In aggregate they occur in about 25% patients with AMD. Wet AMD is due to new growth of abnormal blood vessels under the retina. The new blood vessels are believed to be due to an excessive release of vascular endothelial growth factor (VEGF) by the retinal pigment epithelium(RPE) cells. Wet AMD is now effectively treated with intraocular injections of VEGF inhibitors. Geographic Atrophy, the other form of advanced AMD, represents focal death of the RPE cells and overlying neurosensory retina. There is no current treatment for GA. It is suspected that GA is due in part to a localized inflammatory response, damage to RPE cells and loss of RPE cell function. It may also be speculated that stimulation of RPE cells to release a potent neurotrophic factor, pigment epithelium derived factor (PEDF) may slow progression of GA. In 2008, Dr. Brian McKay identified a receptor, G protein coupled receptor
#143(GPR143), on the surface of RPE cells and discovered that L-DOPA was the natural ligand or stimulator of GPR143. Dr McKay showed that treatment of RPE cells with exogenous L-DOPA resulted in the release of additional PEDF. In subsequent work Dr McKay's group also showed that L-DOPA stimulation of PEDF in RPE cells was also associated with a decrease in VEGF. Thus, Dr McKay hypothesized that exogenous LDOPA may prevent the onset of AMD or progression to wet AMD.
In 2015, Dr McKay and his associates published a paper that showed that patients, who had been treated with L-DOPA, had a delay in the onset of AMD by 8 years, compared to patients who had not been treated with L-DOPA. In addition, those who had AMD and went on to develop wet AMD, did so 5 years later than those with no history of L-DOPA treatment. L-DOPA is an intermediate in the pigmentation pathway. Dr McKay and his associates suggested that the reason darkly pigmented races do not get AMD nearly as frequently as lighter pigmented races, is that they produce more pigment, and thus more L-DOPA to stimulate GPR143 on RPE cells. According to this hypothesis, the stimulated RPE cells release PEDF and decrease VEGF, which together are responsible for the protective effect.
Pharmacology of L-DOPA and carbidopa:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Outcomes Assessor)
盲法说明
All tablets will be identical in appearance. The Director of Research will be aware of treatment assignment. Patients, their Care Providers and all other study staff will be blinded to treatment.
入排标准
- 年龄范围
- 50 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •A diagnosis of dry AMD with geographic atrophy in one or both eyes. In patients with geographic atrophy in both eyes, the eye with the larger area of geographic atrophy will be designated eye A and the eye with the smaller area of geographic atrophy will be designated eye B.
- •Normal or dry AMD of any grade in the second eye;
- •Age 50-85 years;
- •Willingness to maintain AREDS vitamin supplements throughout the study, or remain off these supplements for the duration of the study, if not taking them prior to the study;
- •Signed Informed Consent.
- •Exclusion criteria:
- •Any previous or current use of L-DOPA containing medication or dopamine agonist medication, or any planned use of any of these agents, except for study medication, during the study;
- •Concurrent use of monoamine oxidase (MAO) inhibitors;
- •Any eye condition, disease, or history of trauma in either eye, which can impair vision, except cataract or cataract surgery;
- •BCVA worse than 20/100 in the eye with better BCVA;
- •Current, or history of, neovascular AMD in either eye;
- •Neurologic conditions which can impair vision;
- •Parkinson's Disease;
- •Significant orthostatic hypotension, defined as a drop in systolic blood pressure, immediately upon changing from the supine to standing position, of >19 mmHg, or a symptomatic drop in systolic blood pressure, immediately upon changing from the supine to standing position;
- •Significant ECG abnormalities, as judged by the Investigator;
- •Estimated glomerular filtration rate (eGFR) <20 ml/min;
- •Liver enzymes >3 X the upper limit of normal;
- •HbA1C >9.0;
- •Any other significant lab abnormalities, as judged by the Investigator.
- •Women of childbearing potential;
- •Known retinal hemorrhage;
- •Subjects who are not fluent in English.
排除标准
- 未提供
研究组 & 干预措施
Carbidopa-levodopa 2 tablets daily
carbidopa-levodopa 25-100 mg 2 tablets daily hs
干预措施: carbidopa-levodopa (Drug)
carbidopa-levodopa 6 tablets daily
carbidopa-levodopa 25-100 mg, 2 tablets, 3 times daily, with breakfast, with supper and hs
干预措施: carbidopa-levodopa (Drug)
Placebo
Placebo, 2 tablets, 3 times daily, with breakfast, with supper and hs
干预措施: carbidopa-levodopa (Drug)
结局指标
主要结局
Area of Geographic Atrophy
时间窗: Change over 12 months
area of retinal geographic atrophy measured by fundus autofluorescence
次要结局
- Best Corrected Visual Acuity by ETDRS(Change over 12 months)
- Central retinal thickness(Change over 12 months)
- Development of neovascular macular degeneration(New diagnosis during 12 months of treatment)